Developing a whole-host model to study combination drug therapy for tuberculosis

Inhalation of Mycobacterium tuberculosis (Mtb) leads to tuberculosis (TB) disease, one of the biggest threats to global health. The first-line drug regimen consists of four antibiotics – rifampin, isoniazid, pyrazinamide and ethambutol – for six to nine months. Additional antibiotics are also available and may be suitable for drug-resistant TB or may offer the possibility of shorter treatment times. Assessment of the efficacy of all potential drug combinations is only feasible with the use of a computational model. Previously, we compared efficacy of several drug regimens using our agent-based model GranSim to follow treatment of a single granuloma, solid structures in Mtb-infected lungs containing immune cells and bacteria. To simulate multiple heterogeneous granulomas simultaneously along with immune cells generated within lymph nodes and passing through blood, we developed a whole-host model, HostSim, which is able to capture the progress of infection in the lungs and the recruitment of immune cells. We then integrated pharmacodynamic and pharmacokinetic modeling into HostSim to investigate effects of various drug regimens on multiple heterogeneous granulomas. The model is calibrated against in vitro and in vivo data. This model can aid in identifying optimal treatment regimens for further testing in animal models of TB.